1. Technical Field of the Invention
The present invention relates to novel phenylurea compound inhibitors of the SOAT-1 enzyme (abbreviation of “Sterol-O-Acyl Transferase-1”, also called ACAT-1 from “Acylcoenzyme A Cholesterol Acyl Transferase”). It also relates to their formulation into pharmaceutical compositions useful for application in human or veterinary medicine, or in cosmetic compositions, as well as their non-therapeutic applications.
2. Description of Background and/or Related and/or Prior Art
Compounds having a SOAT-1 inhibiting type of activity are widely described in the literature, as having activities in the regulation of the biological processes involving cholesterol and its derivatives. These properties endow compounds of this class with considerable potential in the treatment or prevention of a great many pathologies, and more particularly in dermatology and in cardiovascular diseases or disorders of the central nervous system. Most of the biological effects of the inhibitors of SOAT-1 are mediated by prevention of the synthesis of cholesterol esters by the SOAT-1 enzyme. Among the documents of the prior art describing SOAT-1 inhibiting molecules, exemplary are WO 96/10559, EP-0370740, EP-0424194, U.S. Pat. No. 4,623,663, EP-0557171, U.S. Pat. No. 5,003,106, EP-0293880, EP-0433662, U.S. Pat. No. 5,106,873 which describe compounds for treating arteriosclerosis or hypercholesterolaemia. The therapeutic potential of the inhibitors of SOAT-1 in the treatment of cardiovascular diseases and in particular of hypercholesterolaemia and arteriosclerosis is also described in Kharbanda R. K. et al., in Circulation. 2005, 11, 804. The potential of the inhibitors of SOAT-1 for the treatment of Alzheimer's disease has also been reported in the literature, for example by Puglielli, L. et al., in Nature Neurosciences 2003, 6 (4), 345.
For their part, U.S. Pat. Nos. 6,133,326, 6,271,268, and WO 2005/034931 describe SOAT-1 inhibiting compounds for inhibiting the production of sebum. In the field of dermatology in particular, it is particularly advantageous to prevent excessive production of sebum and all the associated conditions.
Sebum is produced by the sebaceous glands. The highest concentration of sebaceous glands occurs on the face, the shoulders, the back and the scalp. Sebum is secreted on the surface of the skin, where it plays a very important physiological role, associated with maintenance of the dermal barrier and of a microenvironment permitting regulation of the bacterial and fungal flora of the skin.
Hyperproduction of sebum is generally associated with a skin or scalp of greasy appearance, causing discomfort and a poor appearance. Moreover, hyperproduction of sebum can give rise to seborrhoeic dermatitis and is associated with an increased incidence or severity of acne. The cholesterol esters produced in the sebaceous gland by SOAT-1 are one of the components of sebum, among several classes of lipids including triglycerides, esters of waxes and squalenes, as described by Nikkari, T., in J Invest Derm 1974, 62, 257. Inhibition of this enzyme or of other acyltransferases may therefore make it possible to inhibit the production of sebum. U.S. Pat. No. 6,133,326 describes, notably, the inhibition of sebum by inhibitors of ACAT-1 (also called SOAT-1). However, to date, no treatment utilizing said inhibitors is commercially available. The only treatments providing cure or relief of disorders associated with hyperseborrhoea are systemic hormonal treatments or systemic treatment with 13-cis retinoic acid, and the side effects of these treatments limit their field of application considerably. There is therefore a clear medical and cosmetic need for treatment of the disorders and pathologies associated with hyperproduction of sebum.